| 1. |
- Budczies, Jan, et al.
(författare)
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Remodeling of central metabolism in invasive breast cancer compared to normal breast tissue - a GC-TOFMS based metabolomics study
- 2012
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Changes in energy metabolism of the cells are common to many kinds of tumors and are considered a hallmark of cancer. Gas chromatography followed by time-of-flight mass spectrometry (GC-TOFMS) is a well-suited technique to investigate the small molecules in the central metabolic pathways. However, the metabolic changes between invasive carcinoma and normal breast tissues were not investigated in a large cohort of breast cancer samples so far.RESULTS: A cohort of 271 breast cancer and 98 normal tissue samples was investigated using GC-TOFMS-based metabolomics. A total number of 468 metabolite peaks could be detected; out of these 368 (79%) were significantly changed between cancer and normal tissues (p<0.05 in training and validation set). Furthermore, 13 tumor and 7 normal tissue markers were identified that separated cancer from normal tissues with a sensitivity and a specificity of >80%. Two-metabolite classifiers, constructed as ratios of the tumor and normal tissues markers, separated cancer from normal tissues with high sensitivity and specificity. Specifically, the cytidine-5-monophosphate / pentadecanoic acid metabolic ratio was the most significant discriminator between cancer and normal tissues and allowed detection of cancer with a sensitivity of 94.8% and a specificity of 93.9%.CONCLUSIONS: For the first time, a comprehensive metabolic map of breast cancer was constructed by GC-TOF analysis of a large cohort of breast cancer and normal tissues. Furthermore, our results demonstrate that spectrometry-based approaches have the potential to contribute to the analysis of biopsies or clinical tissue samples complementary to histopathology.
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| 2. |
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| 3. |
- Halje, Pär, et al.
(författare)
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Levodopa-induced dyskinesia is strongly associated with resonant cortical oscillations.
- 2012
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Ingår i: The Journal of Neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 32:47, s. 16541-16551
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Tidskriftsartikel (refereegranskat)abstract
- The standard pharmacological treatment for Parkinson's disease using the dopamine precursor levodopa is unfortunately limited by gradual development of disabling involuntary movements for which the underlying causes are poorly understood. Here we show that levodopa-induced dyskinesia in hemiparkinsonian rats is strongly associated with pronounced 80 Hz local field potential oscillations in the primary motor cortex following levodopa treatment. When this oscillation is interrupted by application of a dopamine antagonist onto the cortical surface the dyskinetic symptoms disappear. The finding that abnormal cortical oscillations are a key pathophysiological mechanism calls for a revision of the prevailing hypothesis that links levodopa-induced dyskinesia to an altered sensitivity to dopamine only in the striatum. Apart from having important implications for the treatment of Parkinson's disease, the discovered pathophysiological mechanism may also play a role in several other psychiatric and neurological conditions involving cortical dysfunction.
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| 4. |
- Ivica, Nedjeljka, et al.
(författare)
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Design of a high-density multi-channel electrode for multi-structure parallel recordings in rodents
- 2014
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Ingår i: 2014 36th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC). - 1557-170X. ; , s. 393-396
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Konferensbidrag (refereegranskat)abstract
- In neurophysiology, investigating brain connectivity within and between different brain structures is of fundamental importance for understanding nervous system function and its relation to behavior. Yet, parallel recordings in multiple brain structures is highly challenging, especially in rodents, which are most commonly employed in neurophysiological research but rather small in size. In this study, the design and manufacturing of a high-density multi-channel electrode for chronic, multi-structure parallel recordings in rats is presented and exemplified with functional neuronal recordings from 128 recording channels, placed bilaterally in eight different brain structures, in an awake, freely moving animal.
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| 5. |
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| 6. |
- Richter, Ulrike, et al.
(författare)
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A novel approach to propagation pattern analysis in intracardiac atrial fibrillation signals
- 2011
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Ingår i: Annals of Biomedical Engineering. - : Springer Science and Business Media LLC. - 1573-9686 .- 0090-6964. ; 39, s. 310-323
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study is to investigate propagation patterns in intracardiac signals recorded during atrial fibrillation (AF) using an approach based on partial directed coherence (PDC), which evaluates directional coupling between multiple signals in the frequency domain. The PDC is evaluated at the dominant frequency of AF signals and tested for significance using a surrogate data procedure specifically designed to assess causality. For significantly coupled sites, the approach allows also to estimate the delay in propagation. The methods potential is illustrated with two simulation scenarios based on a detailed ionic model of the human atrial myocyte as well as with real data recordings, selected to present typical propagation mechanisms and recording situations in atrial tachyarrhythmias. In both simulation scenarios the significant PDCs correctly reflect the direction of coupling and thus the propagation between all recording sites. In the real data recordings, clear propagation patterns are identified which agree with previous clinical observations. Thus, the results illustrate the ability of the novel approach to identify propagation patterns from intracardiac signals during AF, which can provide important information about the underlying AF mechanisms, potentially improving the planning and outcome of arrhythmia ablation.
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| 7. |
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| 8. |
- Richter, Ulrike, et al.
(författare)
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Mechanisms underlying cortical resonant states: implications for levodopa-induced dyskinesia
- 2013
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Ingår i: Reviews in the Neurosciences. - : Walter de Gruyter GmbH. - 0334-1763 .- 2191-0200. ; 24:4, s. 415-429
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Tidskriftsartikel (refereegranskat)abstract
- A common observation in recordings of neuronal activity from the cerebral cortex is that populations of neurons show patterns of synchronized oscillatory activity. However, it has been suggested that neuronal synchronization can, in certain pathological conditions, become excessive and possibly have a pathogenic role. In particular, aberrant oscillatory activation patterns have been implicated in conditions involving cortical dysfunction. We here review the mechanisms thought to be involved in the generation of cortical oscillations and discuss their relevance in relation to a recent finding indicating that high-frequency oscillations in the cerebral cortex have an important role in the generation of levodopa-induced dyskinesia. On the basis of these insights, it is suggested that the identification of physiological changes associated with symptoms of disease is a particularly important first step toward a more rapid development of novel treatment strategies.
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| 9. |
- Richter, Ulrike, et al.
(författare)
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Propagation pattern analysis during atrial fibrillation based on sparse modeling
- 2012
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Ingår i: IEEE Transactions on Biomedical Engineering. - 1558-2531. ; 59:5, s. 1319-1328
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Tidskriftsartikel (refereegranskat)abstract
- Abstract in UndeterminedIn this study, sparse modeling is introduced for the estimation of propagation patterns in intracardiac atrial fibrillation (AF) signals. The estimation is based on the partial directed coherence function, derived from fitting a multivariate autoregressive model to the observed signal using least-squares (LS) estimation. The propagation pattern analysis incorporates prior information on sparse coupling as well as the distance between the recording sites. Two optimization methods are employed for estimation of the model parameters, namely, the adaptive group least absolute selection and shrinkage operator (aLASSO), and a novel method named the distance-adaptive group LASSO (dLASSO). Using simulated data, both optimization methods were superior to LS estimation with respect to detection and estimation performance. The normalized error between the true and estimated model parameters dropped from 0.20 +/- 0.04 for LS estimation to 0.03 +/- 0.01 for both aLASSO and dLASSO when the number of available data samples exceeded the number of model parameters by a factor of 5. For shorter data segments, the error reduction was more pronounced and information on the distance gained in importance. Propagation pattern analysis was also studied on intracardiac AF data, the results showing that the identification of propagation patterns is substantially simplified by the sparsity assumption.
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| 10. |
- Richter, Ulrike, et al.
(författare)
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Propagation pattern analysis during atrial fibrillation based on the adaptive group LASSO
- 2011
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Ingår i: Engineering in Medicine and Biology Society, EMBC, 2011 Annual International Conference of the IEEE. - 1557-170X. - 9781424441211 ; 3, s. 5535-5538
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Konferensbidrag (refereegranskat)abstract
- The present study introduces sparse modeling for the estimation of propagation patterns in intracardiac atrial fibrillation (AF) signals. The estimation is based on the partial directed coherence (PDC) function, derived from fitting a multivariate autoregressive model to the observed signals. A sparse optimization method is proposed for estimation of the model parameters, namely, the adaptive group least absolute selection and shrinkage operator (aLASSO). In simulations aLASSO was found superior to the commonly used least-squares (LS) estimation with respect to estimation performance. The normalized error between the true and estimated model parameters dropped from 0.20±0.04 for LS estimation to 0.03±0.01 for aLASSO when the number of available data samples exceeded the number of model parameters by a factor of 5. The error reduction was more pronounced for short data segments. Propagation patterns were also studied on intrac-ardiac AF data, the results showing that the identification of propagation patterns is substantially simplified by the sparsity assumption.
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| 11. |
- Richter, Ulrike
(författare)
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Spatial Characterization and Estimation of Intracardiac Propagation Patterns During Atrial Fibrillation
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This doctoral thesis is in the field of biomedical signal processing with focus on methods for the analysis of atrial fibrillation (AF). Paper I of the present thesis addresses the challenge of extracting spatial properties of AF from body surface signals. Different parameters are extracted to estimate the preferred direction of atrial activation and the complexity of the atrial activation pattern. In addition, the relation of the spatial properties to AF organization, which is quantified by AF frequency, is evaluated. While no significant correlation between the preferred direction of atrial activation and AF frequency could be observed, the complexity of the atrial activation pattern was found to increase with AF frequency. The remaining three papers deal with the analysis of the propagation of the electrical activity in the atria during AF based on intracardiac signals. In Paper II, a time-domain method to quantify propagation patterns along a linear catheter based on the detected atrial activation times is developed. Taking aspects on intra-atrial signal organization into account, the detected activation times are combined into wavefronts, and parameters related to the consistency of the wavefronts over time and the activation order along the catheter are extracted. Furthermore, the potential relationship of the extracted parameters to established measures from body surface signals is investigated. While the degree of wavefront consistency was not reflected by the applied body surface measures, AF frequency could distinguish between recordings with different degrees of intra-atrial signal organization. This supports the role of AF frequency as an organization measure of AF. In Paper III, a novel method to analyze intracardiac propagation patterns based on causality analysis in the frequency domain is introduced. In particular, the approach is based on the partial directed coherence (PDC), which evaluates directional coupling between multiple signals in the frequency domain. The potential of the method is illustrated with simulation scenarios based on a detailed ionic model of the human atrial cell as well as with real data recordings, selected to present typical propagation mechanisms and recording situations in atrial tachyarrhythmias. For simulated data, the PDC is correctly reflecting the direction of coupling and thus the propagation between all recording sites. For real data, clear propagation patterns are identified which agree with previous clinical observations. Thus, the results illustrate the ability of the novel approach to identify propagation patterns from intracardiac signals during AF which can provide important information about the underlying AF mechanisms, potentially improving the planning and outcome of ablation. However, spurious couplings over long distances can be observed when analyzing real data comprised by a large number of simultaneously recorded signals, which gives room for further improvement of the method. The derivation of the PDC is entirely based on the fit of a multivariate autoregressive (MVAR) model, commonly estimated by the least-squares (LS) method. In Paper IV, the adaptive group least absolute selection and shrinkage operator (LASSO) is introduced in order to avoid overfitting of the MVAR model and to incorporate prior information such as sparsity of the solution. The sparsity can be motivated by the observation that direct couplings over longer distances are likely to be zero during AF; an information which has been further incorporated by proposing distance-adaptive group LASSO. In simulations, adaptive and distance-adaptive group LASSO are found to be superior to LS estimation in terms of both detection and estimation accuracy. In addition, the results of both simulations and real data analysis indicate that further improvements can be achieved when the distance between the recording sites is known or can be estimated. This further promotes the PDC as a method for analysis of AF propagation patterns, which may contribute to a better understanding of AF mechanisms as well as improved AF treatment.
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| 12. |
- Santana, Maxwell B, et al.
(författare)
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Spinal cord stimulation alleviates motor deficits in a primate model of Parkinson disease.
- 2014
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Ingår i: Neuron. - : Elsevier BV. - 0896-6273. ; 84:4, s. 716-722
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Tidskriftsartikel (refereegranskat)abstract
- Although deep brain electrical stimulation can alleviate the motor symptoms of Parkinson disease (PD), just a small fraction of patients with PD can take advantage of this procedure due to its invasive nature. A significantly less invasive method-epidural spinal cord stimulation (SCS)-has been suggested as an alternative approach for symptomatic treatment of PD. However, the mechanisms underlying motor improvements through SCS are unknown. Here, we show that SCS reproducibly alleviates motor deficits in a primate model of PD. Simultaneous neuronal recordings from multiple structures of the cortico-basal ganglia-thalamic loop in parkinsonian monkeys revealed abnormal highly synchronized neuronal activity within each of these structures and excessive functional coupling among them. SCS disrupted this pathological circuit behavior in a manner that mimics the effects caused by pharmacological dopamine replacement therapy or deep brain stimulation. These results suggest that SCS should be considered as an additional treatment option for patients with PD.
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| 13. |
- Waldkirch, Eginhard S., et al.
(författare)
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Expression of cyclic AMP-dependent protein kinase isoforms in human cavernous arteries : functional significance and relation to phosphodiesterase type 4
- 2010
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Ingår i: Journal of Sexual Medicine. - : Oxford University Press (OUP). - 1743-6095 .- 1743-6109. ; 7:6, s. 2104-2111
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: The cyclic adenosine monophosphate-dependent protein kinase (cAK) is considered a key protein in the control of smooth muscle tone in the cardiovascular system. There is evidence that erectile dysfunction might be linked to systemic vascular disorders and arterial insufficiency, subsequently resulting in structural changes in the penile tissue. The expression and significance of cAK in human cavernous arteries (HCA) have not been evaluated.AIMS: To evaluate the expression of cAK isoforms in HCA and examine the role of cAK in the cyclic adenosine monophosphate (cAMP)- and cyclic guanosine monophosphate (cGMP)-mediated control of penile vascular smooth muscle.METHODS: The expression and distribution of phosphodiesterase type 4 (PDE4) and cAK isoforms in sections of HCA were investigated by means of immunohistochemistry and Western blot analysis. The effects of the cAK inhibitor Rp-8-CPT-cAMPS on the relaxation of isolated preparations of HCA (diameter > 100 µm) induced by rolipram, sildenafil, tadalafil, and vardenafil were studied using the organ bath technique.MAIN OUTCOME MEASURES: Investigate the expression of cAK in relation to α-actin and PDE4 in HCA and evaluate the effects of an inhibition of cAK on the relaxation induced by inhibitors of PDE4 and PDE5 of isolated penile arteries.RESULTS: Immunosignals specific for cAKIα, IIα, and IIβ were observed within the wall of HCA. Double stainings revealed colocalization of cAK with α-actin and PDE4. The expression of cAK isoforms was confirmed by Western blot analysis. The reversion of tension induced by inhibitors of PDE4 and PDE5 of isolated penile vascular tissue were attenuated significantly by Rp-8-CPT-cAMPS.CONCLUSIONS: Our results demonstrate the expression of cAK isoforms in the smooth musculature of HCA and its colocalization with PDE4. A significant role for cAK in the regulation mediated by cAMP and cGMP of vascular smooth muscle tone in HCA can also be assumed.
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